2003 — 2007 |
Muthuswamy, Senthil K |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Early Events of Carcinoma Induced by Erbb Receptors @ Cold Spring Harbor Laboratory
[unreadable] DESCRIPTION (provided by applicant): We know that pathogenesis of cancer begins as hyperplastic lesions, some of which progress to malignancy while other remain benign. The molecular features that differentiate lesions are largely unknown. This is in part due to lack of our understanding of the molecular mechanisms that initiate transformation of epithelial cells in vivo. Loss of growth control and disruption of epithelial architecture are thought to be earliest events in cancer. However, we do not understand how oncogenes coordinately deregulate growth control and architecture to initiate transformation of epithelial cells in vivo. Oncogenes of the ErbB receptor tyrosine kinase family can initiate transformation of epithelia in vivo. However, it has been a challenge to understand how different members of the ErbB family transform epithelial cells because they function by forming homo- and heterodimers amongst themselves, which complicates our ability to dissect out the role played by specific ErbB dimers. We have developed a novel method to control dimerization of ErbB receptors that will allow us to activate specific receptor dimers of choice in normal epithelial cells. We have also adapted a cell culture method to generate three-dimensional, polarized, growth-arrested epithelial cells that share several properties with cells lining the ducts in vivo. Combination of these two approaches provides us with novel and powerful tool to understand the molecular mechanisms by which ErbB receptors transform growth-arrested, polarized epithelial cells. Using our unique system, we will activate various combinations of ErbB receptor dimers to (1) investigate the ability of specific ErbB dimers to induce uncontrolled proliferation and loss of architecture in 3D mammary epithelial acini-like structures and identify the signaling pathways critical for this process (2) identify the mechanisms by which different ErbB homo- and heterodimers affect localization and function of proteins that regulate epithelial cell polarity, and (3) determine the relationship between the ability of ErbB dimers to disrupt cell polarity and their ability to re-initiate proliferation in growth-arrested, polarized epithelial cells. Of particular importance is our capability to uncover novel molecular mechanism involved in initiation of carcinoma and also to identify novel and specific targets for treating patients with ErbB-positive tumors.
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0.903 |
2008 |
Muthuswamy, Senthil K |
R56Activity Code Description: To provide limited interim research support based on the merit of a pending R01 application while applicant gathers additional data to revise a new or competing renewal application. This grant will underwrite highly meritorious applications that if given the opportunity to revise their application could meet IC recommended standards and would be missed opportunities if not funded. Interim funded ends when the applicant succeeds in obtaining an R01 or other competing award built on the R56 grant. These awards are not renewable. |
Mechanisms by Which Polarity Proteins Regulate Initiation and Progression of Brea @ Cold Spring Harbor Laboratory
Almost all malignant breast cancers originate from epithelial cells within glandular structures. Normal epithelial architecture/polarity is critical to maintain the delicate balance between a cell and its microenvironment; disruption of this balance can result in the aberrant cell behavior observed during initiation and progression of carcinoma. In fact, pathologists routinely use changes in cell and tissue architecture to understand cancer progression and make assessments for treatment options. Despite the appreciation of the importance of cell architecture, the mechanism by which cell and tissue architecture is disrupted in carcinoma remains poorly understood. It is likely that understanding the molecular mechanisms by which cell and tissue and architecture is deregulated in carcinoma will not only allow us to have a better understanding of changes in tumor microenvironment but also identify a new class of biomarkers and drug targets. During the past funding period we discovered that oncogenes interact with polarity regulators to disrupt cell polarity and three-dimensional organization of epithelial structures. The interaction was independent of the ability of oncogenes to induce cell proliferation. Surprisingly, the oncogene-polarity genes interaction was required for protecting cells from apoptosis. Thus, polarity genes play important roles in carcinoma. They are required for oncogenes to induce changes in cell and tissue architecture and for protecting cells from death. I think we have just begun to scrape the ice, much remains to be understood on the molecular mechanisms by which polarity pathways cooperate with oncogenes during initiation and progression of carcinoma. In this proposal we build on our results from the previous funding period to address the following: 1) Develop a deeper understanding of the mechanism by which ErbB2 interacts with polarity pathways; (2) Determine how polarity pathways protects cells from apoptosis and what roles does this play during development of drug resistance (3) Determine how polarity pathways cooperate with ErbB2 to promote epithelial to mesenchymal transition and malignant progression. Thus the goal of this proposal is to take a new perspective - understand carcinoma initiation and progression as a function of deregulated cell polarity pathways.
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0.903 |
2009 — 2013 |
Muthuswamy, Senthil K |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Cell Polarity Pathways and Erbb2 Mediated Tumorigenesis @ Cold Spring Harbor Laboratory
DESCRIPTION (provided by applicant): Current therapeutic strategies for breast cancer are mostly aimed at controlling malignant disease. In most cases, these strategies extend a patient's lifespan, but are rarely successful in stopping the cancer. I believe that by gaining an understanding of the molecular mechanisms involved in development of premalignant lesions and progression to malignant cancer, we will be able to devise strategies to treat breast cancer early when there is a greater chance for cure. All invasive breast cancers originate from epithelial cells, which in the normal breast are arranged with a distinct polarized organization within ducts and lobules. Changes in cell polarity and organization are a key criterion used by pathologists in grading cancers, supporting the notion that regulation of cell polarity and tissue organization is a critical component of cancer progression. However, very little is known about the molecular mechanisms that regulate changes in cell polarity. It is my belief that mechanisms by which polarity pathways are altered in cancer represent an untapped area of cancer cell biology that offers tremendous potential for discovery of novel strategies for early diagnosis and treatment to effectively eradicate invasive breast cancer. During the past funding period we discovered that ErbB2 directly interacts with the Par6/aPKC polarity complex. This pathway was required for the ability of ErbB2 to disrupt cell polarity and inhibit cell death, but was dispensable to induce cell proliferation. These results have identified two major roles for polarity pathways in ErbB2 positive breast cancers - 1) to disrupt cell and tissue architecture;2) to inhibit cell death. The latter was an unexpected finding, which was not predicted by all the studies previously performed in Drosophila and Worms. In this proposal we propose to extend on these finding and develop a deeper understanding of the mechanisms by which ErbB2 interacts with the polarity protein and identify the pathways downstream of ErbB2-Par6 polarity complex that regulates cell death. In the process of these studies we will develop robust in vivo models that will not only allow us to determine the in vivo relevance of our finding but will also function as tools for preclinical studies. In addition to the above, we also propose extend the scope and investigate how alterations in polarity pathways promote invasive progression and metastasis. Thus, I believe that our proposal takes an innovative strategy and exploits an unexplored area of cancer biology with the goal of finding a new class of biomarkers and drug targets. PUBLIC HEALTH RELEVANCE: Pathologists routinely use changes in cell and tissue structure to understand cancer progression and make assessments for treatment options. However, the molecular pathways that regulate loss of normal cell and tissue structure is poorly studied. The goal of this proposal is to take a new perspective - understand breast cancer initiation and progression as a function of molecular pathways that regulate cell shape. We use three-dimensional organ cultures and mouse models to accomplish this goal. In addition, we collaborate with pathologists to determine the clinical relevance of our findings. This investigation is likely to identify a novel class of biomarkers and drug targets for premalignant and malignant carcinoma.
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0.903 |
2020 — 2021 |
Denis, Gerald V [⬀] Emili, Andrew Monti, Stefano Muthuswamy, Senthil K |
U01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Multiscale Analysis of Metabolic Inflammation as a Driver of Breast Cancer @ Boston University Medical Campus
Women with breast cancer and co-morbid Type 2 diabetes (T2D) have up to 40% worse overall survival compared to non-diabetic women; this co-morbidity burden is disproportionately high among vulnerable cohorts, such as patients at safety net hospitals in the U.S., where it can affect half of the patient population. Yet, current models of breast tumor progression and immunotherapy are based on data from metabolically healthy cancer patients, ignoring metabolic /inflammatory components of T2D. Preliminary and published data support an overall hypothesis: specific metabolic and immune exhaustion networks in breast cancer patients with co-morbid T2D promote tumor aggressiveness. We propose an innovative multiscale modelling framework to identify these networks by integrating metabolic, inflammatory and immune signatures in multi-omics cancer models encompassing RNA-seq and phosphoproteomics data. We take a systems biology approach to combine innovative computational, clinical and patient-derived tumor organoid experiments to investigate interactions among putative driver genes, T2D and immune exhaustion, with tumor progression/aggressiveness as the primary outcome variable in estrogen receptor-negative (ER-) breast cancer, which has poor prognosis and is highly prevalent among safety net hospital patients. We will model how T2D rewires signaling hubs, nodes and edges in newly diagnosed breast cancer patients, then test these networks in breast organoid models. We will develop a unified model through three Aims: Aim 1: Determine how T2D reprograms immune exhaustion and metabolism in the tumor microenvironment of ER negative (ER-) breast cancer. We will apply RNAseq and scRNAseq to primary ER- breast cancer cells and tumor immune infiltrates to compare three groups of patients (T2D, T2D+ metformin-medicated (T2D+M), non-diabetic (ND) controls) to construct a preliminary network supplemented with TCGA data. Differential gene and pathway analyses will elucidate regulatory relationships and key hubs. We hypothesize that the connectivity of the ER- cluster in T2D will be altered and denser than in ND or T2D+M. Aim 2: We will generate patient-derived organoids, including organoid-primed T cells (OpT), to test the computational model for metabolism and immune checkpoints. We will evaluate mechanistic hypotheses that T2D medications, immune checkpoint-blocking antibodies and chemical inhibitors of BET bromodomain proteins (which regulate checkpoint expression) overcome immune exhaustion to improve OpT cell metabolism and tumor cell killing. TCR sequencing will reveal emergent OpT oligoclonality; deep immunophenotyping will reveal T2D-driven signaling networks. Aim 3: Determine abnormal signaling networks impacting cancer immunity in organoid and OpT models. We will perform deep phosphoproteomic profiling of primary tumors, organoids, circulating T cells and OpT cells, from the three metabolic groups, then use pathway projection and network analyses to refine our integrated model. Together, our unique systems biology approach will capture the complex interactions among tumor, immune infiltrates and metabolic genes to address the cancer burden of T2D.
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0.945 |